The present invention relates to a novel 2,3-disubstituted pyridine derivative exhibiting a phosphodiesterase IV (hereinafter, referred to as PDE IV) inhibitory activity being useful as a medicament, a process for the preparation thereof, a pharmaceutical composition containing the same, and an intermediate therefor.
Hitherto, theophylline or various chemical mediator antagonists have been used as an agent for treatment of asthma, but these agents have defects, for example, they cannot exhibit a sufficient inhibitory effect on bronchoconstriction or a sufficient effect on airway inflammatory and they cannot show a sufficient selectivity from their side effects on the cardiovascular system. Steroids also have been used as an agent for treatment of asthma, and their effects on the airway inflammation are potent but their inhibitory effects on bronchoconstriction is weak, and in addition, serious side effects of steroids have also been predicted. Therefore, it has been desired to develop a novel agent exhibiting an inhibitory effect on bronchoconstriction as well as an effect on the airway inflammation.
PDE IV widely distributes onto the bronchial smooth muscle and inflammatory cells including eosinophil, and it is an enzyme catalyzing the destruction of cyclic AMP (hereinafter, occasionally referred to as cAMP). It has widely been known that by inhibiting PDE IV, the constriction of the bronchial smooth muscle is prevented, and the activation of inflammatory cells is prevented (Current Medicinal Chemistry, vol. 2, p. 561-572 (1995)).
The compounds of the following formulae, for example, Rolipram (U.S. Pat. No. 4,193,926), RP-73401 (WO 92 12961), SB-207499 (WO 93 19749), are exemplified as a representative compound having a PDE IV inhibitory activity. 
In addition, EP 773024 discloses that an N-substituted nicotinamide compound of the following formula (A) exhibits a PDE IV inhibitory activity. 
wherein R3 is 1-piperidyl, phenyl, benzyl, etc., Y is hydrogen, fluoro or chloro, and X is hydrogen, fluoro, chloro, methoxy, trifluoromethyl, cyano, carboxy, methylcarbamoyl, dimethylcarbamoyl or a carbo(C1-C4)alkoxy.
In addition, WO 9845268 discloses that a nictoninamide compound of the following formula (B) exhibits a PDE IV inhibitory activity. 
wherein m is 0 or 1, n is 0 or 1, o is 0, 1, 2, 3, or 4, p is 0 or 1, q is 0, 1, 2, or 3, r is 0, 1, 2, 3, or 4, t is 0 or 1, A is an oxygen atom,  greater than NH, etc., B is an oxygen atom or NH, D is an oxygen atom or NR9, E is CH2, an oxygen atom, NH or S(O)a, R1 is a hydrogen atom, a (C1-C6)alkyl group, a (C3-C7)heterocyclic group, etc., R2, R3 and R4 are a hydrogen atom, a hydroxy group, etc., R5 is a (C3-C7)heterocycle, R6, R7 and R8 are a hydrogen atom, a (C1-C6)alkyl group, etc.
However, conventional PDE IV inhibitors cannot show a sufficient bronchodilating activity, and under such circumstances, it has been desired to develop a novel PDE IV inhibitor exhibiting more potent bronchodilating activity as well as effects on the airway inflammation.
On the other hand, a compound of the above formula (A) or (B) wherein the 3-substituent of the pyridine ring is a pyridylalkyleneoxy group has never been known.
An object of the present invention is to provide a novel 2,3-disubstituted pyridine derivative and a pharmaceutically acceptable salt thereof, which show an excellent PDE IV inhibitory activity.
The present invention relates to a 2,3-disubstituted pyridine derivative of the following formula (I) or a pharmaceutically acceptable salt thereof, a phosphodiesterase IV inhibitor containing said compound as an active ingredient, and a pharmaceutical composition containing the same. 
wherein
A is an oxygen atom, a sulfur atom, CHR1 or NR2, R1 and R2 are a hydrogen atom or a lower alkyl group;
X1 and X2 are the same or different and each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower acyl group, a lower acyloxy group, an amino group, a lower acylamino group, a carbamoyl group, a 5-tetrazolyl group, or a group which can be converted into a hydroxy group in vivo;
Y1 is a hydrogen atom or a lower alkyl group;
Z1 and Z2 are the same or different and each a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono- or di-lower alkylamino group, a lower acylamino group, a lower alkoxycarbonylamino group, a lower alkylsulfonylamino group, a carbamoyl group, a 5-tetrazolyl group, or a group which can be convereted into a hydroxy group in vivo; and
n is an integer of 2 to 4.
The pharmaceutically acceptable salt includes a pharmaceutically acceptable acid addition salt, an alkali metal salt, an alkaline earth metal salt or a salt with an organic base. For example, the acid addition salt includes a salt with an inorganic acid such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc., or a salt with an organic acid such as oxalate, maleate, fumarate, malonate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, gluconate, etc. The alkali metal salt includes, for example, a salt with an inorganic alkali metal such as sodium salt, potassium salt, and the alkaline earth metal salt includes, for example, calcium salt, magnesium salt. The salt with an organic base includes, for example, a salt with ammonia, methylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, dicyclohexylamine.
The present compound of the formula (I) and a pharmaceutically acceptable salt thereof may exist in the form of a hydrate and/or a solvate, and the present invention also includes these hydrates and solvates as well.
The present compounds of the formula (I) may optionally have one or more asymmetric carbon atoms, and the present invention also includes these stereoisomers and a mixture thereof.
When Z1 or Z2 is a hydroxy group and these groups attach to the 2-position or the 4-position of the pyridine ring, the present compounds of the formula (I) may have a keto-enol tautomer, and the present invention also includes these tautomers, and a mixture thereof.
In the compound (I), the group being able to be converted into a hydroxy group in vivo means a group which can be enzymatically or non-enzymatically destructed to a hydroxy group in vivo, for example, one wherein a hydroxy group is acylated, carbonated or carbamated by an acetyl group, a propionyl group, a benzoyl group, an ethoxycarbonyl group, a carbamoyl group, an amino acid residue, etc. Hereinafter, compounds having such groups may occasionally be referred as a prodrug.
The present invention also relates to an intermediate for preparing a 2,3-disubstituted pyridine derivative of the above formula (I), i.e., a pyridine derivative of the following formula (II): 
wherein Z3 is a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group, a lower alkoxy-substituted lower alkyl group, a lower acyl group, a benzyl group, a benzoyl group, or a mono- or di-lower alkoxy-substituted benzoyl group, Z4 is a hydrogen atom, a halogen atom, a cyano group, a lower alkoxycarbonyl group, a lower acyloxy group, a lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, an amino group, a lower alkoxycarbonylamino group, or a lower alkylsulfonylamino group.
The terms used in the specification are explained below.
The xe2x80x9clower alkyl groupxe2x80x9d and the xe2x80x9clower alkyl moietyxe2x80x9d include a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl, etc.
The xe2x80x9chalogeno-lower alkyl groupxe2x80x9d and the xe2x80x9chalogeno-lower alkyl moietyxe2x80x9d include a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, which is substituted by a halogen atom, for example, trifluoromethyl group.
The xe2x80x9ccyclo-lower alkyl groupxe2x80x9d and the xe2x80x9ccyclo-lower alkyl moietyxe2x80x9d include a cyclic alkyl group having 3 to 6 carbon atoms, for example, cyclopentyl and cyclohexyl.
The xe2x80x9clower acyl groupxe2x80x9d and the xe2x80x9clower acyl moietyxe2x80x9d include a straight chain or branched chain alkanoyl group having 1 to 5 carbon atoms, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, and pivaloyl.
The xe2x80x9chalogen atomxe2x80x9d is fluorine atom, chlorine atom, bromine atom, and iodine atom.
The xe2x80x9clower alkoxy groupxe2x80x9d and the xe2x80x9clower alkoxy moietyxe2x80x9d include a straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, and hexyloxy.
The xe2x80x9ccyclo-lower alkoxy groupxe2x80x9d and the xe2x80x9ccyclo-lower alkoxy moietyxe2x80x9d include a cyclic alkoxy group having 3 to 6 carbon atoms, for example, cyclopentyloxy and cyclohexyloxy.
The xe2x80x9clower alkenyl groupxe2x80x9d and the xe2x80x9clower alkenyl moietyxe2x80x9d include a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms, for example, allyl, 2-butenyl, and 3-methyl-2-butenyl.
Among the present compounds (I) of the present invention, preferable one is a compound of the formula (I) wherein A is an oxygen atom, a sulfur atom, CH2 or NH, Z1 and Z2 are the same or different and each a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxyl-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a mono- or di-lower alkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono- or di-lower alkylamino group, a lower acylamino group, a lower alkoxycarbonylamino group, a lower alkylsulfonylamino group, a carbamoyl group, or a group which can be converted into a hydroxy group in vivo, or a pharmaceutically acceptable salt thereof.
More preferable compounds are compounds of the formula (Ia) or a pharmaceutically acceptable salt thereof. 
wherein
A1 is an oxygen atom, a sulfur atom, CH2 or NH;
X11 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, or a lower acyl group;
X21 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group;
Y1 is a hydrogen atom or a lower alkyl group;
Z11 and Z21 are the same or different and each a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a mono- or di-lower alkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono- or di-lower alkylamino group, a lower acylamino group, a lower alkoxycarbonylamino group, a lower alkylsulfonylamino group, a carbamoyl group, or a group which can be converted into a hydroxy group in vivo.
Especially preferable compounds are the following compounds or a pharmaceutically acceptable salt thereof.
2-phenoxy-3-[3-(pyridin-4-yl)propoxy]pyridine;
2-(3-bromophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine;
2-(3-fluorophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine;
2-(3-fluorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine;
2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine;
2-(3-bromophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine;
2-(3-chlorophenoxy)-3-[3-(3-aminopyridin-4-yl)propoxy]pyridine;
2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine;
2-phenoxy-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine;
2-(3-chlorophenoxy)-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine;
2-(3-chlorophenoxy)-3-[3-(3-chloro-5-hydroxypyridin-4-yl)propoxy]pyridine;
2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridin-5-yl)propoxy]pyridine;
2-(3-chlorophenoxy)-3-[3-(3-amino-5-hydroxypyridin-4-yl)propoxy]pyridine;
2-(3-chlorophenoxy)-3-[3-(3-methylsulfonylaminopyridin-4-yl)propoxy]pyridine; and
2-(3-bromophenylthio)-3-[3-(pyridin-4-yl)propoxy]pyridine.
The representative compounds (I) of the present invention are the compounds as listed in the following Table 1 or a pharmaceutically acceptable salt thereof, in addition to the compounds of Examples as disclosed hereinbelow.
The compounds (I) of the present invention may be prepared, for example, by the following processes (a) and (b), as explained below.
Process (a)
The compound of the formula (I) wherein A is an oxygen atom, a sulfur atom or CHR1 may be prepared, if necessary, by protecting by a conventional method a compound of the formula (III): 
wherein A2 is an oxygen atom, a sulfur atom or CHR1, X12 and X22 are the same or different and each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a lower alkoxycarbonyl group, a lower acyl group or a lower acyloxy group, and R1 and Y1 are as defined above,
and a compound of the formula (IV): 
wherein Z12 and Z22 are the same or different and each a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a lower alkoxycarbonyl group, a lower acyloxy group, a benzyloxy group, a benzoyloxy group, a mono- or di-lower alkoxy-substituted benzoyl group, a mono- or di-lower alkoxy-substituted benzoyloxy group, an amino group, a lower alkoxycarbonylamino group or a lower alkylsulfonylamino group, and n is as defined above,
followed by condensing these compounds in the presence of a triphenylphosphine and a dialkyl azodicarboxylate in a suitable solvent, then, if necessary, by removing the protecting groups from the resultant, and further converting the substituents X12, X22, Z12, Z22 to other substituents by a conventional method, if required.
The dialkyl azodicarboxylate includes, for example, dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate, etc. In addition, a trialkylphosphine such as tri-n-butylphosphine, etc. may be used instead of triphenylphosphine. The reaction is preferably carried out at a temperature of from xe2x88x9250xc2x0 C. to 120xc2x0 C., more preferably at a temperature of from 0xc2x0 C. to 80xc2x0 C. The solvent may be tetrahydrofuran, toluene, xylene, dichloromethane, etc.
The compound of the formula (IV) may include a compound of the above formula (II), i.e., a compound of the (IV) wherein one of Z12 and Z22 is bonded to the 3-position of the pyridine ring as OZ3, and the other is bonded to the 4- or 5-position of the pyridine ring as Z4, and a hydroxyalkylene group wherein n is 3 is bonded to the 4- or 5-position of the pyridine ring to which the above Z4 is not bonded.
Process (b)
The compound of the formula (I) wherein A is an oxygen atom, a sulfur atom or NR2 may be prepared by reacting a compound of the formula (V): 
wherein L is a halogen atom or a nitro group, Z13 and Z23 are the same or different and each a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, or a lower alkoxycarbonyl group, and Y1 and n are as defined above,
with a compound of the formula (VI): 
wherein A3 is an oxygen atom, a sulfur atom or NR2, and R2, X12 and X22 are as defined above,
in the presence of a base and a copper catalyst in a suitable solvent, and if necessary, by removing the protecting groups from the resulting compound, and then further followed by converting the substituents X12, X22, Z13, Z23 to other substituents by a conventional method, if required. The base is preferably an alkali metal hydride, an alkali metal carbonate, etc. The copper catalyst may preferably be cuprous iodide, cuprous bromide, cuprous chloride, copper powder, cuprous oxide, cupric bromide, etc. The reaction is carried out at a temperature of from 80xc2x0 C. to 220xc2x0 C., preferably at a temperature of from 100xc2x0 C. to 180xc2x0 C. The solvent may preferably be dimethylformamide, dimethylimidazolidinone, dimethylsulfoxide, dimethylacetamide, pyridine, toluene, xylene, etc.
Processes for preparing the starting compounds for Processes (a) and (b), i.e., the compounds of the formulae (II) to (VI), are explained below.
Process for Preparing the Compound of the Formula (III)
The compound of the formula (III) which is a starting compound for Process (a) wherein A is an oxygen atom, i.e., the compound of the formula (1-4), may be prepared according to the following Scheme 1. Namely, a compound of the formula (1-1) and a compound of the formula (1-2) are reacted in the presence of a base and a copper catalyst in a suitable solvent, and the resulting compound of the formula (1-3) is deprotected to give a compound of the formula (1-4). 
wherein Q is a lower alkyl group, a cyclo-lower alkyl group, a lower alkoxy-substituted lower alkyl group, a lower alkenyl group, a benzyl group, or a tetrahydropyranyl group, and L, X12, X22 and Y1 are as defined above.
The compound of the formula (1-1) or (1-2) may be commercially available ones or may be prepared by a conventional method. The base may be an alkali metal hydride, an alkali metal carbonate, etc. The copper catalyst may preferably be cuprous iodide, cuprous bromide, cuprous chloride, copper powder, cuprous oxide, cupric bromide, etc. The reaction is carried out at a temperature of from 80xc2x0 C. to 220xc2x0 C., preferably at a temperature of from 100xc2x0 C. to 180xc2x0 C. The solvent may be dimethylformamide, dimethylimidazolidinone, dimethylsulfoxide, dimethylacetamide, pyridine, toluene, xylene, etc.
The starting compound for Process (a), a compound of the formula (III) wherein A is a sulfur atom, i.e., a compound of the formula (2-3) may be prepared according to the following Scheme 2. Namely, a compound of the formula (2-1) and a compound of the formula (2-2) are reacted in a suitable solvent to give a compound of the formula (2-3). 
wherein L, X12, X22 and Y1 are as defined above.
The compound of the formula (2-1) or (2-2) may be commercially available ones or may be prepared by a conventional method. The reaction is carried out at a temperature of from 0xc2x0 C. to 200xc2x0 C., preferably at a temperature of from 50xc2x0 C. to 130xc2x0 C. The solvent may be dimethylformamide, dimethylimidazolidinone, dimethylsulfoxide, dimethylacetamide, toluene, xylene, tetrahydrofuran, etc.
The starting compound for Process (a), a compound of the formula (III) wherein A is CHR1, i.e., a compound of the formula (3-6) or (3-8) may be prepared according to the following Scheme 3. Namely, a compound of the formula (3-1) is converted to a lithium salt compound of the formula (3-1a), which is further reacted with a compound of the formula (3-2) to give a compound of the formula (3-3). When R1 is a hydrogen atom, a compound of the formula (3-3) is oxidized to give a compound of the formula (3-4), which is further subjected to reduction to give a compound of the formula (3-5). The compound (3-5) is further deprotected to give a compound of the formula (3-6). When R1 is a lower alkyl group, the compound (3-3) is subjected to reduction to give a compound of the formula (3-7), which is further deprotected to give a compound of the formula (3-8). 
wherein L1 is a bromine atom or a iodine atom, and R1, Q, X12, X22 and Y1 are as defined above.
The compound of the formula (3-1) or (3-2) may be commercially available ones or may be prepared by a conventional method. The compound of the formula (3-1) can be converted to a corresponding lithium salt thereof by reacting with a base such as n-butyl lithium in a suitable solvent. The reaction is preferably carried out at a temperature of from xe2x88x92150xc2x0 C. to 100xc2x0 C., preferably at a temperature of from xe2x88x9280xc2x0 C. to 0xc2x0 C. The solvent may be toluene, xylene, tetrahydrofuran, diethyl ether, dioxane, etc.
A compound of the formula (3-2) is added to a reaction solution containing the compound of the formula (3-1a) thus obtained and reacted. The reaction is carried out at a temperature of from xe2x88x92150xc2x0 C. to 100xc2x0 C., preferably at a temperature of xe2x88x9280xc2x0 C. to 0xc2x0 C.
The compound of the formula (3-4) is obtained by reacting a compound of the formula (3-3) wherein R1 is a hydrogen atom in the presence of an oxidizing agent such as activated manganese dioxide, etc. in a suitable solvent. The reaction is carried out at a temperature of from xe2x88x9220xc2x0 C. to 120xc2x0 C., preferably at a temperature of from 0xc2x0 C. to 100xc2x0 C. The solvent may be toluene, tetrahydrofuran, dioxane, methylene chloride, hexane, etc.
The reduction of the compound of the formula (3-4) is carried out in the presence of hydrazine and a base in a suitable solvent. The base may be an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc., and the solvent may be ethylene glycol, diethylene glycol, etc. The reaction is carried out at a temperature of from 0xc2x0 C. to 220xc2x0 C., preferably at a temperature of from 100xc2x0 C. to 200xc2x0 C.
The compound of the formula (3-7) is obtained by subjecting a compound of the formula (3-3) wherein R1 is a lower alkyl group to catalytic reduction in the presence of palladium carbon, and if necessary, in the presence of an acid catalyst such as hydrochloric acid, acetic acid, perchloric acid, etc. in a suitable solvent under hydrogen atmosphere. The reaction is carried out at a temperature of from xe2x88x9240xc2x0 C. to 110xc2x0 C., preferably at a temperature of from 0xc2x0 C. to 70xc2x0 C. The solvent may be methanol, ethanol, ethyl acetate, toluene, xylene, tetrahydrofuran, dioxane, etc.
The removal of a protecting group from the compound (3-5) and the compound (3-7) is carried out in the presence of a suitable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, camphor-sulfonic acid, etc. in a suitable solvent such as water, methanol, ethanol, isopropanol, acetic acid, etc. The reaction is carried out at a temperature of from xe2x88x9250xc2x0 C. to 100xc2x0 C., preferably at a temperature of from 20xc2x0 C. to 70xc2x0 C.
Process for Preparing a Compound of the Formula (II) or the Formula (IV)
The starting compound for Process (a), i.e. the compound of the formula (IV) may be commercially available one or may be prepared according to the following Scheme 4. Besides, the compound of the formula (II) which is within the scope of the compound of the formula (IV), i.e., the compound of the formula (IV) wherein one of Z12 and Z22 is bonded to the 3-position of the pyridine ring as OZ3, and the other is bonded to the 4- or 5-position of the pyridine ring as Z4, and a hydroxyalkylene group wherein n is 3 is bonded to the 4- or 5-position of the pyridine ring to which said Z4 is not bonded may be prepared similarly. 
wherein E is a bromine atom or a iodine atom, G is a lower alkyl group, a lower alkoxy-substituted lower alkyl group, an allyl group, a benzyl group or a tetrahydropyranyl group, Z14, Z24 are a halogen atom, Z15, Z25 are the same or different and each a halogen atom, a cyano group, a lower alkoxy group, a cyclo-lower alkoxy group, a lower alkoxycarbonyl group, or a benzyloxy group, and Z13, Z23 and Q are as defined above.
Among the starting compounds (IV) for Process (a), the compound of the formula (IV) wherein n is 2 or 4 is obtained by reacting a compound of the formula (4-1) with trimethylsilylmethyl magnesium chloride in a suitable solvent, converting the resulting product into a compound of the formula (4-2) by placing it under acidic conditions, further by subjecting the compound (4-2) to hydroboronation reaction, and to subsequently oxidation and hydrolysis to give a compound of the formula (4-3), and if necessary, followed by converting Z13 and Z23 by a conventional method.
The compound of the formula (4-1) may be commercially available one or may be prepared by a conventional method. The reaction of the compound (4-1) with trimethylsilylmethyl magnesium chloride is preferably carried out at a temperature of from xe2x88x92150xc2x0 C. to 100xc2x0 C., preferably at a temperature of from xe2x88x9270xc2x0 C. to 0xc2x0 C. The solvent may be toluene, xylene, tetrahydrofuran, diethyl ether, dioxane, etc.
The compound (4-2) thus obtained is subjected to hydroboronation in the presence of a hydroboronating agent such as a complex of borane-pyridine, a complex of borane-tetrahydrofuran, or 6-borabicyclo[3.3.1]nonane, etc. in a suitable solvent, and then further subjected to oxidation and a subsequent hydrolysis under basic conditions. The hydroboronation reaction is carried out at a temperature of from xe2x88x92150xc2x0 C. to 100xc2x0 C., preferably at a temperature of from xe2x88x9270xc2x0 C. to 50xc2x0 C. The solvent may be tetrahydrofuran, diethyl ether, dioxane, etc. The oxidation reaction and the subsequent hydrolysis are carried out by adding an aqueous solution of an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc. to the reaction solution of hydroboronation, and then by using an aqueous hydrogen peroxide solution. The reaction is carried out at a temperature of from xe2x88x92100xc2x0 C. to 100xc2x0 C., preferably at a temperature of from xe2x88x9270xc2x0 C. to 50xc2x0 C.
Among the starting compounds (IV) for Process (a), the compound of the formula (IV) wherein n is 3 is prepared by reacting a compound (4-4) with an alkali metal salt of a trialkylphosphonoacetate in a suitable solvent to give the compound (4-5), which is further subjected to catalytic hydrogenation, and further subjecting the resulting compound (4-6) to hydride reduction to give the compound (4-7), and if necessary, followed by converting Z13, Z23 by a conventional method.
The compound (4-4) may be commercially available one or may be prepared by a conventional method. The reaction of the compound (4-4) is carried out by reacting an alkali metal salt of a trialkylphosphonoacetate, which is obtained by reacting a trialkylphosphonoacetate such as trimethylphosphonoacetate, triethylphosphonoacetate, etc. with an alkali metal hydride such as sodium hydride, potassium hydride, etc. in a suitable solvent. The reaction is carried out at a temperature of from xe2x88x9250xc2x0 C. to 100xc2x0 C., preferably at a temperature of from xe2x88x9220xc2x0 C. to 70xc2x0 C. The solvent may be toluene, xylene, tetrahydrofuran, diethyl ether, dioxane, etc.
The compound (4-5) thus obtained may be converted into a compound of the formula (4-6) by catalytic reduction in the presence of a palladium carbon under hydrogen atmosphere. The reaction is carried out at a temperature of from xe2x88x9240xc2x0 C. to 110xc2x0 C., preferably at a temperature of from 0xc2x0 C. to 70xc2x0 C. The solvent may be methanol, ethanol, ethyl acetate, toluene, xylene, tetrahydrofuran, dioxane, etc.
Further, the compound (4-6) is subjected to reduction by using a reagent such as lithium aluminum hydride, diisobutyl aluminum hydride, etc., in a suitable solvent. The reaction is carried out at a temperature of from xe2x88x9250xc2x0 C. to 100xc2x0 C., preferably at a temperature of from 0xc2x0 C. to 70xc2x0 C. The solvent may be toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, etc.
Among the starting compounds (IV) for Process (a), the compound of the formula (IV) wherein n is 3 may also be prepared by reacting a compound of the formula (4-8) with ethylene oxide in the presence of a base to give a compound of the formula (4-7), and if necessary, followed by converting Z13 and Z23 by a conventional method.
The compound (4-8) may be commercially available one or may be prepared by a conventional method. The compound (4-8) may be converted into a compound of the formula (4-7) by treating with a base such as lithium diisopropylamide, lithium hexamethyldisilazide, sodium amide, etc. in a suitable solvent to give a corresponding alkali metal salt thereof, followed by reacting with ethylene oxide. The reaction is carried out at a temperature of from xe2x88x92120xc2x0 C. to 100xc2x0 C., preferably at a temperature of from xe2x88x9280xc2x0 C. to 20xc2x0 C. The solvent may be toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, etc.
Among the starting compounds (IV) for Process (a), the compound of the formula (IV) wherein n is 3 and the 4-position of the pyridine ring is a propanol group may be prepared by reacting a compound of the formula (4-9) with a compound of the formula (4-10) in the presence of a base, if necessary, converting Z14 of the resulting compound of the formula (4-11) by a conventional method, and removing a protecting group to give a compound of the formula (4-12), if necessary, followed by converting Z15 and Z25 by a conventional method.
The compound (4-9) and the compound (4-10) may be commercially available ones or may be prepared by a conventional method. The compound of the formula (4-11) may be prepared by treating the compound of the formula (4-9) with a base such as lithium diisopropylamide, lithium hexamethyldisilazide, sodium amide, etc. in a suitable solvent to give an alkali metal salt thereof, and further reacting with the compound of the formula (4-10). The reaction is carried out at a temperature of from xe2x88x92120xc2x0 C. to 100xc2x0 C., preferably at a temperature of from xe2x88x9280xc2x0 C. to 20xc2x0 C. The solvent may be toluene, xylene, diethyl ether, tetrahydrofuran, dioxane, etc.
Process for Preparing a Compound of the Formula (V)
The starting compound (V) for Process (b), which is the same compound as a compound of the formula (5-3), may be prepared according to the following Scheme 5. Namely, a compound of the formula (5-1) and a compound of the formula (5-2) are reacted in the presence of a triphenylphosphine and a dialkyl azodicarboxylate in a suitable solvent to give a compound of the formula (5-3). 
wherein L, Y1, Z13, Z23 and n are as defined above.
The compound (5-1) may be commercially available one or may be prepared by a conventional method. The dialkyl azodicarboxylate includes dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate, etc. A trialkylphosphine such as tri-n-butylphosphine, etc., may be used instead of a triphenylphosphine. The reaction is carried out at a temperature of from xe2x88x9250xc2x0 C. to 120xc2x0 C., preferably at a temperature of from 0xc2x0 C. to 80xc2x0 C. The solvent may be tetrahydrofuran, toluene, xylene, dichloromethane, etc.
The compound (5-2) may be commercially available one or may be prepared according to the reaction scheme as shown in Scheme 4, in a similar manner as the preparation of the compound of the formula (4-3), the compound (4-7) and the compound (4-12) as mentioned above.
Process for Preparing a Compound of the Formula (VI)
The starting compound (VI) for Process (b) may be commercially available one or may be prepared by a conventional method.
Pharmacological Experiments
The pharmacological experiments were done on the representative compounds of the present compounds. The results and the pharmacological activities of the present compounds are explained as follows.
Experiment 1: PDE IV Inhibitory Activity Test
The PDE IV inhibitory activity test was carried out according to a method using eosinophils prepared from the abdomen of guinea pig (Souness, J. E. et al., Biochem. Pharmacol. vol. 42, p. 937 (1991)). That is, a homogenizing buffer (10 ml, components: 20 mM Tris-HCl buffer (pH 7.5); 2 mM magnesium chloride; 1 mM dithiothreitol, 5 mM ethylenediamine tetraacetate disodium; 250 mM sucrose; 20 xcexcM p-tosyl-l-lysine-chloromethylketone; 10 xcexcg/ml Leupeptine) was added to 5xc3x97107 cells, and the mixture was centrifuged. To the residue was added a solubilizing buffer (10 ml, sodium deoxycholate (final concentration: 0.5%) and sodium chloride (final concentration: 100 mM) were added to the above homogenizing buffer), and the mixture was centrifuged again. The supernatant was subjected to ultrafiltration using Molcut-II (manufactured by Japan Millipore Limited), and the fraction on the membrane was collected by adding a homogenizing buffer (10 ml) to give an enzyme preparation. Inhibitory activity against the enzyme was determined by comparing the hydrolysis rates of a substrate, cAMP (manufactured by Nacalai Tesque Inc.), by the above enzyme fraction between in the test compound-treated group and the vehicle group. In addition, a 50% inhibitory concentration, i.e., IC50, was obtained from a concentration-activity curve of a test compound. The compounds of Examples of the present invention as listed in Table 2 were used as a test compound, and Rolipram RP-73401 and SB-207499, which are known to exhibit a PDE IV inhibitory activity, were used as a control compound. The results are shown in Table 2.
As is clear from Table 2, the present compounds of the formula (I) exhibit a potent inhibitory activity against PDE IV isolated and purified from guinea pig eosinophils.
Experiment 2: Inhibitory Effect on Antigen-induced Bronchoconstriction
Hartley male guinea pigs were actively sensitized by intraperitoneally administering an ovalbumin (manufacture by Sigma). Four weeks thereafter, the animals were anesthetized with Nembutal (50 mg/kg, i.p., manufactured by Dainabot Co., Ltd.), and a cannula was inserted at the airway, and the bronchoconstriction response of the animals under artificial respiration was observed. The response of the airway was measured by Konzett-Roessler method (Naunyn-Schmiedebergs, Arch. Exp. Pathol. Pharmacol., vol. 195, p. 71 (1940)). A test compound (the compounds of Examples of the present invention as listed in Table 3) was orally administered to the animals one hour prior to the administration of the antigen (i.e., ovalbumin, 0.05%/physiological saline solution, i.v.). Only the compound of Example 31 was orally administered 2 hours prior to the administration of the antigen. The inhibitory rate (%) caused by the test compound was calculated by comparing the bronchoconstriction response of the test compound-treated group with that of the control group to which only a solvent was administered. The results are shown in Table 3.
As is shown in Table 3, the present compounds of the formula (I) exhibited a potent inhibitory activity against the bronchoconstriction of guinea pig induced by the antigen.
As is clear from the above Pharmacological Experiments, the compounds (I) of the present invention show a potent PDE IV inhibitory activity as well as an excellent bronchodilating activity.
Besides, the present compounds (I) of the present invention are low toxic. In an acute toxicity test, for example, the compound of Example 31 never showed any toxicity even at a dose of 2000 mg/kg.
The compounds (I) of the present invention can be administered as a PDE IV inhibitor either orally, parenterally or rectally. The compounds of the present invention can also be administered by transpulmonary infiltration, oral mucous administration, trans-nasal mucous administration. The dose of the compounds of the present invention varies according to the administration routes, the conditions, ages of the patients, etc., or by the object of the administration, i.e., prophylaxis or treatment, but it is usually in the range of 0.01-100 mg/kg/day, preferably in the range of 0.1-50 mg/kg/day.
The compounds (I) of the present invention are usually administered in the form of a pharmaceutical preparation, which is prepared by mixing thereof with a pharmaceutically acceptable carrier or diluent. The pharmaceutically acceptable carrier or diluent may be any conventional ones being usually used in the pharmaceutical field, and do not react with the compounds (I) of the present invention. Suitable examples of the pharmaceutically acceptable carrier or diluent are, for example, lactose, glucose, mannitol, dextrin, starch, white sugar, magnesium metasilicate aluminate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, calcium carboxylmethylcellulose, ion exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium laurylsulfate, glycerin, glycerin fatty acid ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, nonionic surfactant, propyleneglycol, water, etc.
The pharmaceutical preparation is, for example, tablets, capsules, granules, powders, syrups, suspensions, suppositories, gels, injection preparations, inhalants, nasal drops, etc. These preparations may be prepared by a conventional method. In the preparation of liquids, the compound of the present invention may be dissolved or suspended in water or a suitable other solvent, when administered. Tablets and granules may be coated by a conventional method. In the injection preparations, it is preferable to dissolve the compound (I) in water, but if necessary, by using an isotonic agent, and further, a pH adjuster, a buffering agent or a preservative may be added thereto.
These preparations may contain the compound (I) of the present invention at a ratio of at least 0.01%, preferably at a ratio of 0.05-70%. These preparations may also contain other therapeutically effective compounds as well.
In addition, these preparations may be used together with an antiallergic agent, a steroid, a xcex22-stimulant, an anticholinergic agent, if necessary.